Implantable enzyme-based monitoring systems having improved longevity due to improved exterior surfaces

ABSTRACT

An implantable enzyme-based monitoring system suitable for long term in vivo use to measure the concentration of prescribed substances such as glucose is provided. In one embodiment, the implantable enzyme-based monitoring system includes at least one sensor assembly, an outer membrane surrounding the sensor assembly and having a window therein, and a polymeric window cover affixed to the outer membrane and covering the window. Preferably, the outer membrane of the monitoring system is silicone and the window cover is a polymer of 2-hydroxyethyl methacrylate (HEMA), N,N,-dimethylaminoethyl methacrylate (DMAEMA) and methacrylic acid (MA). Also provided herein is an implantable enzyme-based monitoring system having at least one sensor assembly, an outer membrane surrounding the sensor assembly and a coating affixed to the exterior surface of the outer membrane, wherein the coating resists blood coagulation and protein binding to the exterior surface of the outer membrane. Preferably, the coating is polyethylene glycol (PEG) and heparin in an 80:20 molar ratio. Finally, provided herein is a method of coating the exterior surface of the outer membrane of an implantable enzyme-based monitoring system comprising the steps of forming hydroxyl groups on the silicone surface by plasma etching; reacting the silicone surface with amino functionalized silane, thereby forming amino groups on the silicone surface; simultaneously, covalently binding polyethylene glycol (PEG) and heparin to the amino groups; and ionically binding heparin to the monitoring system surface.

BACKGROUND OF THE INVENTION

The present invention relates to implantable monitoring systems for thecontinuous in vivo measurement of biochemical substances, and moreparticularly to improved implantable enzyme-based glucose monitoringsystems, small enough to be implanted through the lumen of a catheter orhypodermic needle, that measure the amount and rate of change of glucosein a patient's blood over an extended period of time.

Glucose is an important source of energy in the body and the sole sourceof energy for the brain. Glucose is stored in the body in the form ofglycogen. In a healthy person, the concentration of glucose in the bloodis maintained between 0.8 and 1.2 mg/ml by a variety of hormones,principally insulin and glucagon. If the blood-glucose concentrationfalls below this level neurological and other symptoms may result, suchas hypoglycemia. Conversely, if the blood-glucose level is raised aboveits normal level, the condition of hyperglycemia develops, which is oneof the symptoms of diabetes mellitus. The complications associated withboth of these disorders, particularly if left uncorrected, can result inpatient death. Thus, measuring and maintaining the concentration ofglucose in the blood at a proper level is critically important for goodhealth and longevity.

Unfortunately, some individuals are physically unable to maintain theproper level of glucose in their blood. For such individuals, theconcentration of glucose in the blood can usually be altered, asrequired, to maintain health. For example, a shot of insulin can beadministered to decrease the patient's blood glucose concentration, orconversely, glucose may be added to the blood, either directly, asthrough injection or administration of an intravenous (IV) solution, orindirectly, as through ingestion of certain foods or drinks.

Before a patient's glucose concentration can be properly adjusted,however, a determination must be made as to what the current bloodglucose concentration is and whether that concentration is increasing ordecreasing. Many implantable glucose monitoring systems have beendescribed that are designed to provide continuous measurement of apatient's blood glucose concentration. See for example, U.S. Pat. Nos.3,539,455; 3,542,662; 4,484,987; 4,650,547; 4,671,288; 4,703,756;4,890,620; 5,165,407; and 5,190,041. Most of these systems are based onthe "enzyme electrode" principle where an enzymatic reaction, involvingglucose oxidase, is combined with an electrochemical sensor, to measureeither oxygen or hydrogen peroxide, and used to determine theconcentration of glucose in a patient's blood.

Generally, enzyme-based glucose monitoring systems, whether implantableor not, use glucose oxidase to convert glucose and oxygen to gluconicacid and hydrogen peroxide (H₂ O₂). An electrochemical oxygen detectoris then employed to measure the concentration of remaining oxygen afterreaction of the glucose; thereby providing an inverse measurement of theblood glucose concentration. A second enzyme, catalase, is optionallyincluded with the glucose oxidase to catalyze the decomposition of thehydrogen peroxide to water, in order to prevent interference in themeasurements from the H₂ O₂.

Thus, this system of measuring glucose requires that glucose be thelimiting reagent of the enzymatic reaction. Where the system is to beused in vivo, this requirement can, and often does, pose a seriousproblem because, on a molar basis, the concentration of free oxygen invivo is typically much less than that of glucose. This "oxygen deficit"prevents the exhaustion of glucose in the area of the enzymatic portionof the system and thus, results in an inaccurate determination ofglucose concentration. Further, such an oxygen deficit can contribute toother performance related problems for the sensor assembly, includingdiminished sensor responsiveness and undesirable electrode sensitivity.See for example, the discussion in Gough et al., in Two-DimensionalEnzyme Electrode Sensor for Glucose, Vol 57 Analytical Chemistry pp 2351et seq. (1985), incorporated by reference herein.

Attempts to solve the oxygen deficit problem, associated with in vivoglucose monitoring systems have previously been presented and areprimarily based upon either reduction of the enzyme catalytic activityor regulation of the diffusion of glucose and oxygen through the use ofspecialized membranes. See for example, U.S. Pat. No. 4,484,987, Gough,D., hereby incorporated by reference, in its entirety. These solutions,however, have their own disadvantages. For example, reduction of theenzymatic activity of the monitoring system requires either a reducedconcentration of enzyme or a thinner layer of active enzyme, both ofwhich tend to shorten the useful life of the enzymatic sensor byreducing the amount of useful enzyme. Alternatively, a longer thinnerlayer of enzyme can be employed within the sensor assembly in order tolocally reduce the enzymatic activity without loss of useful life to thesensor, but this tends to slow the responsiveness of the sensor and/orrequires a larger (i.e. longer) sensor, which are both undesirable.

Use of specialized membranes to control the diffusion of glucose andoxygen into the sensor assembly, can also present problems. For example,as discussed in U.S. Pat. No. 5,322,063 issued to Allen et al. andincorporated by reference herein, in its entirety, controlling thediffusion of the glucose and oxygen through the use of specializedmembranes can lead to slower responsiveness of the sensor and/orunintentional poisoning of the sensor and electrodes caused by migrationof undesirable substances through the specialized membranes to thesensor. In particular, to the degree the specialized membrane comprisesa hybrid of two different membrane types, having numerous junctionsbetween two or more disparate membranes, concerns arise as to theintegrity of such junctions, the appropriate ratio of the two membranesto one another and the appropriate configuration of the hybrid (i.e.,for example, "islands" of one membrane type within and each surroundedby the other membrane type or alternating "stripes" of membrane types).

An additional concern that arises when a monitoring system is intendedfor use within the body of a patient, especially where it is to be usedlong term, relates to the biocompatibility of the system. The protectivemechanisms of the body attempt to shield the body from the invasion ofthe monitoring system which is perceived as an unwanted foreign object.These protective mechanisms include, for example, encapsulation of theforeign object by the growth of isolating tissue and coagulation ofblood on and around the foreign object. Obviously, encapsulation ofand/or blood coagulation around all or part of the implantable sensorcan significantly reduce or completely terminate the functionality ofthe device.

Often, the exterior surface of implantable monitoring systems arecomposed of silicone rubber, which is a reasonably biocompatablematerial. However, silicone rubber has been shown to induce thrombosisand encapsulation when compared to living endothelium. Many differentapproaches have been utilized to enhance the biocompatibility ofsilicone rubber and similar polymeric materials. However, presently, itis unclear exactly what the relationships of surface chemistry andmorphology are to blood/body compatibility. This could be due to severalfactors. First, polymer surfaces often are not well characterized.Second, additives, processing aids and the like may have migrated to ormay have been left behind at the polymer surface; thereby contributingto the unpredictable nature of the surface. Furthermore, even if thepolymer is pure, it can have varying surface configurations. The polymersurface may not be homogeneous, or coatings, if any, may not beuniformly applied, or the surface, itself may have developed cracks, allof which can contribute to the incompatibility of the surface with thebody.

With some degree of success, polyethylene glycol (PEG) has been used tocoat polymeric surfaces in order to repel proteins from the surfaceafter implantation. Similarly, heparin has been either covalently boundor ionically bound to polymeric surfaces in order to prevent bloodcoagulation thereabout after implantation. However, ionically boundheparin is gradually released from the implant surface providing onlyshort-term anticoagulant effect, and covalently bound heparin, whileremaining bound to the surface for longer periods of time, is not aseffective an anticoagulant. Thus, where the object to be implanted isintended to remain for a long period of time, the anticoagulant ofchoice is covalently bound heparin.

While finding solutions to the problem of biocompatibility can be quitedifficult, since proper operation of the sensor requires that certainmembranes be in contact with the patient's blood, still what is neededare membranes that are biocompatible yet maintain their functionality orthat may be treated, for example by application of an appropriatecoating, to possess these characteristics. Additionally, an enzyme-basedglucose monitoring system designed to protect against the problem ofoxygen deficit while providing quick, accurate and continuous glucoseconcentration readings over a long term is desirable.

SUMMARY OF THE INVENTION

The subject matter described and claimed herein advantageously addressesthese and other needs by providing an implantable monitoring system,particularly an implantable enzyme-based monitoring system, havingimproved biocompatibility and, therefore, sensor longevity whilemaintaining and even further improving the sensor's reliability,accuracy, and responsiveness to measuring the concentration of one ormore prescribed substances, such as glucose, within a patient's blood.In particular, the monitoring system described herein employs improvedconfigurations and provides for specialized treatment of the exteriorsurfaces of the implantable monitoring systems, which exterior surfacetreatment may be used in conjunction with almost any implantablemonitoring system. The improved configurations include the use of awindow through which the substance of interest is able to diffuse intothe system. The window optimizes blood access to the enzyme and/orsensor assembly, thereby improving the accuracy and responsiveness ofthe sensor assembly. Additionally, the improved configurations include aselectively permeable membrane cover for the window which, among otherthings, may be used to prevent unwanted substances from diffusing intothe monitoring system, thereby improving the accuracy of the system,and/or to prevent the loss of enzyme and/or other substances from withinthe monitoring system. Additional advantages to such a window cover willbe apparent to those of skill in the art. Further improvements describedherein include tapered exterior surfaces proximate the window whichpermit uniform flow of blood over the window, thereby preventingstagnation of blood at or near the side windows; use of multiple sensorassemblies, preferably rotationally displaced with respect to oneanother, and non-linear overall configurations of the monitoring system,such as arcuate, spiral or helical configurations wherein the windows ofthe monitoring system are positioned within the interior facing surfacesof the non-linear configurations. Such additional modifications eachimprove the accuracy of the monitoring system by increasing the samplesize and distribution and/or by preventing the body from interferingwith access to the window within the system.

A still further important and advantageous feature of the preferredembodiment of the implantable monitoring system contemplated herein is aprotective coating, and method of its application, which coating isplaced on the exterior surface of all or selected portions of monitoringsystem in order to improve the biocompatibility of the monitoring systemby preventing tissue growth and/or formation of blood clots on theassembly. The preferred coating materials include a combination of ananti-coagulant, to prevent or reduce blood clot formation on the sensorsurface, and an anti-binding compound, to prevent or reduce proteinbinding (i.e. tissue growth) to the sensor surface. In a particularlypreferred embodiment, use of heparin in combination with polyethyleneglycol (PEG) to achieve this improved biocompatibility is described.

These and other objects, features and advantages of the presentinvention will become apparent to those skilled in the art upon areading of the following detailed description when taken in conjunctionwith the drawings wherein there is shown and described illustrativeembodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

In the following detailed description, reference will be made to theattached drawings in which:

FIG. 1 is a cut away side view of a portion of a preferred embodiment ofan implantable, enzyme-based glucose monitoring system, generallyshowing one embodiment of the sensor assembly thereof and specificallyillustrating the polymeric window cover and exterior surface coating asdisclosed herein;

FIG. 2 is a cut away side view of a portion of a preferred embodiment ofan implantable enzyme-based glucose monitoring system, generally showingan alternative embodiment of the sensor assembly thereof andspecifically illustrating the polymeric window cover and exteriorsurface coating as disclosed herein;

FIG. 3 is a schematic of the preferred derivatization of heparindescribed herein;

FIG. 4 is a schematic of the preferred process of covalent attachment ofpolyethylene glycol and heparin to the exterior surface of themonitoring system;

FIG. 5 is a schematic of the preferred process of ionic attachment ofheparin to the monitoring system surface; and

FIG. 6 is a partial view of an alternative embodiment of the implantablemonitoring system placed in a blood vessel illustrating a non-linearconfiguration, that prevents the windows of the system from beingsituated against the blood vessel wall and blocking blood accessthereto.

FIG. 7 is a partial view of an alternative embodiment of the implantablemonitoring system having the multiple sensor assemblies, as indicated bythe multiple windows illustrated, which sensor assemblies (and thereforewindows) are rotationally displaced with respect to one another.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The following description is of the best mode presently contemplated forcarrying out the invention. For example, a preferred embodimentdescribed herein is directed to an implantable enzyme-based glucosemonitoring system. It will be appreciated by those of skill in the artthat the improvements described herein may be used for implantablemonitoring systems other than those that are enzyme-based and/or otherthan those designed to measure glucose concentrations. Thus, thisdescription is not to be taken in a limiting sense, but is made merelyfor the purpose of describing the general principles of the invention.The scope of the invention should be determined with reference to theclaims.

The numbering between Figures is consistent, such that the same itemillustrated in more than one Figure bears the same identifying number ineach Figure.

DEFINITIONS

As used herein, the term sensor assembly refers to that portion of themonitoring system that is directly involved in sensing the concentrationof the substance(s) being measured, that is the substrate and associatedelectronics, membranes, enzyme(s) and solutions. An enzyme-basedmonitoring system, as contemplated herein, may, and preferably does,include more than one sensor assembly. In each of FIGS. 1 and 2, asingle sensor assembly is illustrated within the outer membrane of themonitoring system. Thus, the outer membrane (and window therein), windowcover and exterior surface coating are not encompassed by the term"sensor assembly" as used herein.

As used herein, the term implantable monitoring system refers to thewhole implantable device. Thus, an implantable monitoring system (orsimply, monitoring system) includes at least one sensor assembly housedwithin an outer membrane. In the most preferred embodiments themonitoring system has more than one sensor assembly and the outermembrane has at least one window associated with each sensor assembly,which window is covered by a window cover and which outer membrane andwindow cover are coated with a coating to resist blood coagulation andprotein binding thereto.

It is noted that the term biocompatible, as used herein, refers tonon-toxicity. As is readily apparent to those of skill in the art, it isimportant that the materials used to manufacture the monitoring system,at least to the degree they come in contact with the patient's body, notbe toxic to the patient into whom the system is implanted. Thus, forexample, any coatings added to the exterior surface of the monitoringsystem should be non-toxic to the patient as well as be able towithstand the stresses of constant blood flow thereacross.

It is also noted that the coatings described herein are designed toresist and/or prevent thrombosis and/or tissue growth at the surface ofthe implanted monitoring system. Thus, reference to the"anti-coagulation" properties of the coating are synonymous with theanti-thrombosis properties thereof, and reference to the"anti-encapsulation" properties of the coating are synonymous with theanti-tissue growth properties thereof. In a preferred embodiment, theprimary characteristic of the coating that provides anti-tissue growthproperties is the ability of the coating to prevent/resist proteinbinding thereto. However, coatings capable of preventing tissue growthabout the exterior surface of the monitoring system through other meansare likewise contemplated herein. Thus, it is the function of thecoating, to resist and/or prevent blood coagulation and/or to preventtissue growth, that is most important to the present invention.

DESCRIPTION

FIGS. 1 and 2 illustrate the portion of two alternative implantableglucose monitoring systems wherein a sensor assembly is located. Each ofthese illustrated monitoring systems show preferred embodiments of thewindow, window covering and exterior coating as described and claimedherein. The alternative sensor assembly configurations are illustrativeof specific examples of improved implantable monitoring systems asherein described.

In preferred embodiments, the monitoring system includes more than onesensor assembly. The sensor assemblies are preferably strung together ina daisy chain fashion, for example as is detailed in U.S. patentapplication Ser. No. 08/928,867, Gord, et al., "Daisy-Chainable Sensorsand Stimulators for Implantation in Living Tissue", filed Dec. 9, 1997,now U.S. Pat. No. 5,999,848, granted Dec. 7, 1999, which is incorporatedherein in its entirety.

Such a multi-sensor monitoring system advantageously permits multiple,simultaneous and/or contemporaneous concentration readings which therebysignificantly increase the accuracy of the monitoring system. In orderto further improve the accuracy of the preferred, multi-sensormonitoring system, and as described further below, the sensor assembliesare rotationally displaced relative to one another resulting indiffering orientations within the patient's body and thus an increasedvariation in the sampling.

For detailed discussions of the systems contemplated for use with thesubject matter described herein, especially those designed formonitoring in vivo glucose concentrations see, for example, U.S. patentapplication Ser. No. 08/444,300, Schulman, et al., entitled "GlucoseSensor Assembly", now U.S. Pat. No. 5,999,848, granted Dec. 7, 1999;U.S. Pat. No. 5,497,772, Schulman, et al.; and U.S. patent applicationSer. No. 08/953,817, filed Oct. 20, 1997, Schulman, et al., "ImplantableEnzyme-Based Monitoring Systems Adapted for Long Term Use" now pending,each of which patent applications and patents is hereby incorporated, byreference, in its entirety.

FIGS. 1 and 2 each illustrate a portion of a monitoring system havingthe polymeric window covering and exterior surface coating ascontemplated herein. These figures also show, in a general manner,alternative sensor assembly configurations that may be used within themonitoring system. The primary difference between the two sensorassemblies illustrated in FIGS. 1 and 2 is the location of themicroprocessor and associated microelectronics on the same substrate asthe electrodes, as illustrated in FIG. 2, or elsewhere, as in FIG. 1.With respect to FIG. 1, the microprocessor and microelectronics arepreferably located outside the patient's body as described, for example,in U.S. Pat. No. 5,660,163, issued to Schulman, et al. on Aug. 26, 1997,hereby incorporated by reference in its entirety.

Turning then to FIG. 1, illustrated is a substrate 10 having fourelectrodes, a first working electrode 12, a reference electrode 14, acounter electrode 16 and a second working electrode 18, affixed thereto.Preferably, the two working electrodes 12 and 18 are most distant eachother on the substrate; whereas the reference 14 and counter 16electrodes are located in any convenient position. Surrounding theelectrodes, and forming a chamber thereabout, is a first membrane 20that is selectively permeable. In preferred embodiments this firstmembrane 20 is hydrophobic and oxygen permeable. An electrolyte solution22 is contained within the chamber and bathes the electrodes therein.Adjacent the first membrane 20 is an outer membrane 24 that also isselectively permeable. Again, in preferred embodiments, the outermembrane 24 is oxygen permeable and hydrophobic. It is this outermembrane 24 that comes in direct contact with the patient's body uponimplantation and thus must be biocompatible.

A window or pocket 28 is formed within the outer membrane 24 at a pointadjacent the second working electrode 18. Preferably, the window isformed with smooth, tapered surfaces or edges, thereby maintaining acontrolled, uniform flow of blood over the window while preventing anystagnation of blood near the window and thereby minimizing the formationof blood clots. In this preferred embodiment, an enzyme solution 34 iscontained within the window/pocket 28. The enzyme solution may begelatinous, such as is described by Gough in U.S. Pat. No. 4,890,620,incorporated herein in its entirety, or it may be a fluid solution, suchas that described in co-pending U.S. Pat. No. 6,081,736, filed Oct. 20,1997, Schulman, et al., "Implantable Enzyme-Based Monitoring SystemsAdapted for Long Term Use", incorporated by reference, above.Additionally, it is noted that the window 28 may be either a holecompletely through the outer membrane 24 or a pocket within the outermembrane which is open to the exterior of the monitoring system.

A polymeric cover 36 covers the opening of the window or pocket. Thecover 36 is preferably biocompatible, permeable to oxygen and glucose,has a mechanical strength comparable to that of the outer membrane 24and adheres well to the material used to form the outer membrane 24.This cover serves the dual purpose of preventing unwanted substancesfrom entering the monitoring system and thereby possibly contaminatingthe sensor assembly or interfering with its operation and of keeping inthe enzyme solution 34 and/or other reagents contained within themonitoring system.

The window cover 36 is associated with the outer membrane 24. This maybe accomplished by adhering the window cover 36 to the exterior surfaceof the outer membrane 24 near the edge of the window 28, as illustratedin FIG. 1, or it may be accomplished by forming the window cover 36within the window 28, as illustrated in FIG. 2. Where the latterpositioning is used, the window cover is adhered to the inner edge ofthe window 28, which inner edge is preferably tapered, as previouslydescribed. It is noted that adherence of the window cover 36 to theouter membrane 24 may be accomplished in a number of ways. What iscritical is that the adherence be such that the window cover 36 remainsin place despite the constant flow of blood there-across.

Additionally, in this preferred embodiment, some or all of the exteriorsurface of the monitoring system has an exterior coating applied theretothat includes an anti-coagulant and/or anti-tissue growth solution 38.Most preferably, this exterior coating is applied to the entire exteriorsurface of the monitoring system, including the exterior surface of thepolymeric cover. Such a coating is advantageous both for improving thebiocompatibility of the monitoring system and for preventing bloodclotting and/or tissue growth in the area of the polymeric window cover.For example, if the edges of the window cover are rough or irregular,both blood clotting and tissue growth will be more likely to occur.Thus, application of the exterior coating in this area can reduce thelikelihood of or prevent such problems, thereby increasing the in vivolongevity of the monitoring system.

Of course, it is not necessary to, and under certain circumstances maybe advantageous not to, coat the entire exterior monitoring system withsuch an exterior coating. For example, the window cover may restcompletely within the window/pocket opening and not extend above thetapered side-walls of the window/pocket. When this is so, the exteriorcoating may preferably be applied only to the exterior surface of themonitoring system and not to the window cover. Other such alternativeswill be readily appreciable to those of skill in the art and arelikewise contemplated herein. Both the polymeric window cover andexterior coating/treatment 38 of the outer membrane 24 are described indetail in the Examples that follow.

In operation of the monitoring system, oxygen diffuses into the systemthrough both the outer membrane 24 and polymeric cover 36; whereas,glucose diffuses into the system only through the polymeric cover 36.Glucose and oxygen react in the presence of the enzyme 34 within thewindow/pocket 28 and the unreacted oxygen continues to diffuse throughthe system to contact the second working electrode 18. Simultaneously,oxygen diffuses into the monitoring system, in the areas where no enzymeis located, through to the first working electrode 12. Thus, the firstworking electrode 12 measures the background levels of oxygen and thesecond working electrode 18 measures the level of unreacted oxygen,thereby providing a determination of the in vivo glucose concentration.

As stated above, FIG. 2 illustrates an alternative embodiment of thesensor assembly employed in a glucose monitoring system according to thepresent invention. As with the sensor assembly of FIG. 1, this sensorassembly has a substrate 10 with four electrodes 12, 14, 16 and 18affixed thereto and a first membrane 20 that forms a chamber or pocketthereabout within which an electrolyte solution 22 is contained. In thispreferred embodiment, however, an intermediate membrane 26 is addedbetween the first membrane 20 and outer membrane 24. This intermediatemembrane 24 is preferably a hydrophobic, oxygen permeable membrane andis positioned adjacent the first working 12, reference 14 and counter 16electrodes, only. The intermediate membrane 26 is not adjacent thesecond working electrode 18, rather, the intermediate membrane 26 helpsto form a chamber adjacent the second working electrode 18 within whichthe enzyme solution 34 is contained.

Also illustrated in this alternative embodiment, is a microelectronicsassembly 30 affixed to the substrate 10 on the side opposite theelectrodes 12, 14, 16 and 18. A lid 32 covers the microelectronicsassembly 30 and is affixed to the substrate 10 so as to provide ahermetic seal therewith. The details of this particular sensor assemblyembodiment, are in co-pending U.S. patent application Ser. No.08/953,817, entitled "Implantable Monitoring Systems Adapted for LongTerm Use In vivo," filed simultaneously herewith. This application isincorporated, in its entirety, by reference herein.

As with the system illustrated in FIG. 1, that of FIG. 2 has an outermembrane 24, surrounding the interior workings just described. A window28 is formed in the outer membrane 24 at a point adjacent the secondworking electrode 18, as described with respect to FIG. 1. It is notedthat the window 28 of this embodiment is necessarily a hole through theouter membrane 24 and is not a pocket. Covering the window 28 opening,is a polymeric cover 36 as described above and detailed in the Examplesbelow. The outer membrane is constructed of a hydrophobic and oxygenpermeable material, such as silicon rubber, and an exterior coating isapplied to reduce and/or prevent blood coagulation and tissue formationthereon. Such exterior coating is also detailed in the Examples below.

Thus, the embodiment depicted in FIG. 2 operates in generally the samemanner as that described for the FIG. 1 embodiment. For a detaileddiscussion of the configuration and operation of the monitoring systemsgenerally illustrated herein, see U.S. Pat. No. 5,497,772, Schulman, etal.; U.S. Pat. No. 4,890,620, Gough, et al.; and U.S. patent applicationSer. No. 08/953,817, filed Oct. 20, 1997, Schulman, et al. each of whichhave been previously referred to and incorporated in their entiretyherein.

Turning to the Examples, described are the materials and methods forcarrying out preferred embodiments of the present invention. Alternativematerials that function in substantially the same manner will be evidentto those of skill in the art and are likewise contemplated herein.

EXAMPLE 1 Polymeric Window Cover

As stated above, the materials of the polymeric cover for the window inthe outer membrane of the preferred, glucose monitoring system must bechosen to be biocompatible, glucose and oxygen permeable and have amechanical strength comparable to, and be able to adhere well to, theouter membrane. In preferred embodiments, the outer membrane is formedof silicone rubber, thus it is this material to which the polymericwindow cover must adhere and comparable to which the cover's mechanicalstrength should be.

Preferable herein, is a polymeric system of 2-hydroxyethyl methacrylate(HEMA), N,N,-dimethylaminoethyl methacrylate (DMAEMA) and methacrylicacid (MA) in weight ratios of 50:25:25. Following is a preferred methodof preparing this co-polymer.

Preparation of Polymeric Window Covering

To a 20 ml scintillation vial the following purified components areadded then well agitated:

    ______________________________________                                        2-Hydroxyethyl methacrylate                                                                         0.50 g  (±0.01 g)                                    Methacrylic acid      0.25 g  (±0.005 g)                                   Dimethylamino ethyl methacrylate                                                                    0.25 g  (±0.005 g)                                   Ethylene glycol       1.0 g   (±0.05 g)                                    Ethylene glycol dimethacrylate                                                                      0.1 g   (±0.005 g)                                   Camphoquinone         3.5 mg  (±0.1 mg)                                    Escolol 507           5.0 mg  (±0.1 mg)                                    ______________________________________                                    

Once mixed by agitation, the window covering is stored at roomtemperature in the absence of light. When ready to be used, the windowcovering is applied to the window using a syringe and photo-polymerizedin situ.

EXAMPLE 2 Surface Modification of Exterior of Monitoring System

Modification of the silicone exterior of the monitoring system toimprove the longevity of the system by making it more resistant to bloodcoagulation and tissue growth was accomplished by first, etching thesurface of the silicone; then introducing amino groups on to the etchedsilicone surface; next, simultaneously, covalently grafting heparin andpolyethylene glycol (PEG) to the surface; and finally, ionically bindingadditional heparin to the surface. In a preferred embodiment the finalmolar ratio of heparin to PEG is 20 to 80, as described further, below.

Once completed, the resulting monitoring system has the advantage ofpowerful, short-term anti-coagulation protection, provided by theionically bound heparin, which slowly dissipates over time as the ionicbonds break and the heparin leaches from the system; and the system hasstable long-term anti-coagulant protection from the covalently boundheparin. The covalently bound PEG operates to minimize the proteindeposition and fibrin sheath formation which is commonly observed onlong-term implantable catheter surfaces, such as that of the monitoringsystem.

Plasma etching of the outer surface of the silicone outer membrane, inorder to introduce hydroxyl groups thereto, was performed using standardmethods. Amino groups were then introduced to the etched surface byreaction with functionalized silane. In order to achieve an efficientcovalent grafting of heparin to the surface of the silicone, a waterinsoluble ionic complex of heparin with lipid molecules (Hep-L) wasformed. Being soluble in many organic solvents, the complex wasefficiently derivatized by tosylating one hydroxyl group per repeat unitof heparin. PEG was tosylated by standard methods, as known to those ofskill in the art and the tosylated PEG and Hep-L complexes weresubsequently reacted with the amino functionalized outer membraneexterior surface. Next, the lipid molecules were cleaved from theheparin by incubating the outer membrane with dilute HBr (pH=5), andfinally, heparin was ionically bound to the exterior outer membranesurface, using standard techniques.

FIGS. 3, 4 and 5 illustrate these processes, schematically. FIG. 3 is aschematic of the derivatization of heparin. FIG. 4 is a schematic of thecovalent grafting of heparin and PEG to the surface of the monitoringsystem, and FIG. 5 is a schematic of the ionic binding of heparin tothat surface.

FIG. 6 illustrates a partial view of one embodiment of the preferredimplantable monitoring system 48, having a non-linear configuration, ascontemplated herein. Such non-linear configurations are particularlyadvantageous in that they prevent the sensing elements from being orbecoming placed or oriented against the blood vessel wall 56. Placementof the monitoring system against the blood vessel promotes stagnation ofthe blood and limits the accuracy of glucose level measurements becausethe window(s) and underlying glucose sensing elements are notcontinually exposed to free flowing blood. By adding curves to theoverall monitoring system configuration, it can, at most, contact thewalls of the blood vessel in only small areas rather than along its fulllength. It is noted that it may be necessary to also modify the shape ofthe sensor assembly substrate, for example to also be arcuate.

Thus, FIG. 6 illustrates a portion of an implantable monitoring system,as contemplated herein, wherein the shape has an arcuate configuration,with the windows 50 placed on the interior facing surface of the arcs52. The exterior facing surfaces 54 of the arcs are, then, necessarilysituated closer to the blood vessel wall 56. This specially designedconfiguration provides uniform and consistent blood flow over thewindows of the monitoring system. In this preferred embodiment, threeglucose sensor assemblies are present, as illustrated by the threewindows 50 which are adjacent each sensor assembly. It will beappreciated by those of skill in the art that various monitoring systemconfigurations may be employed to achieve the same result as is achievedby the S-shape shown in FIG. 6. For example, a spiral shape may be used,wherein the windows of the monitoring system are preferably positionedon the interior face of the spiral. Similarly, more than one sensorassembly may be positioned along the interior face of a single arc/curvein the monitoring system configuration. Such alternatives are equallycontemplated herein.

FIG. 7 illustrates a partial view of yet another alternative embodimentof the implantable monitoring system as contemplated herein. Inparticular, FIG. 7 shows an alternative configuration that, like theconfiguration shown in FIG. 6, improves the overall accuracy of themonitoring system by reducing the likelihood that all, or a significantportion of, the sensing elements could be placed or oriented against theblood vessel wall 56. In this embodiment, the windows 50 on the outermembrane of the monitoring system are rotationally displaced, withrespect to one another, around the circumference of the monitoringsystem. The sensor assemblies (not shown) within the monitoring system,therefore, are also rotationally displaced with respect to one anotherand in alignment with the windows. As can be seen in FIG. 7, should themonitoring system come to rest against the vessel wall, only a limitednumber of the windows (and therefore, sensors) will be blocked thereby.Alternative configurations and combinations will be apparent to those ofskill in the art and are likewise contemplated herein. Additionally, itis noted that the monitoring system illustrated in FIG. 6 also requiresthe sensor assemblies to be rotationally displaces with respect to oneanother. The particular embodiment illustrated in FIG. 6, would have thesensor assemblies rotationally displaced at 180° from one another.

From the foregoing, it should be appreciated that the present inventionthus provides an implantable enzyme-based monitoring system adapted forthe continuous in vivo measurement of bio-chemicals, such as glucoseover an extended period of time. Further, it will be apparent thatvarious changes may be made in the form, construction and arrangement ofthe parts thereof without departing from the spirit and scope of theinvention or sacrificing all of its material advantages, the formshereinbefore described being merely exemplary embodiments thereof.

To that end, it is not intended that the scope of the invention belimited to the specific embodiments and processes illustrated anddescribed. Rather, it is intended that the scope of this invention bedetermined by the appending claims and their equivalents.

What is claimed is:
 1. An implantable monitoring system comprising:atleast one enzymatic sensor assembly; an outer membrane surrounding theenzymatic sensor assembly, the outer membrane having at least one windowtherein; and a window cover associated with the outer membrane such thatthe window is covered thereby.
 2. An implantable monitoring systemaccording to claim 1, further comprising an enzyme solution positionedbetween the sensor assembly and the window cover within the outermembrane.
 3. An implantable monitoring system according to claim 2,wherein the enzyme solution comprises glucose oxidase and the windowcover is glucose permeable.
 4. An implantable monitoring systemaccording to claim 1, wherein the window cover is glucose and oxygenpermeable.
 5. An implantable monitoring system according to claim 1 orclaim 4, wherein the window cover comprises a polymeric system of2-hydroxyethyl methacrylate (HEMA), N,N,-dimethylaminoethyl methacrylate(DMAEMA) and methacrylic acid (MA).
 6. An implantable monitoring systemaccording to claim 5, wherein the weight ratios of the components of thepolymeric system are about 50:25:25, for the HEMA, DMAEMA and MA,respectively.
 7. An implantable monitoring system according to claim 1,further comprising a coating on an exterior surface of the outermembrane, which coating resists blood coagulation and protein binding tothe exterior surface of the outer membrane, and wherein the coatingcomprises two components at least one of which is selected from thegroup consisting of heparin and polyethylene glycol.
 8. An implantablemonitoring system according to claim 7, wherein the coating comprisespolyethylene glycol (PEG) and heparin.
 9. An implantable monitoringsystem comprising:at least one sensor assembly; an outer membranesurrounding the sensor assembly, the outer membrane having at least onewindow therein, a window cover associated with the outer membrane suchthat the window is covered thereby; and a coating on the exteriorsurface of the outer membrane, which coating resists blood coagulationand protein binding to the exterior surface of the outer membrane;wherein the coating further comprises at least two active components;and wherein at least one of the components is selected from the groupconsisting of heparin and polyethylene glycol.
 10. An implantablemonitoring system according to claim 9, wherein the coating comprisespolyethylene glycol (PEG) and heparin.
 11. An implantable monitoringsystem according to claim 10, wherein the molar ratio of PEG to heparinin the coating is 80 to
 20. 12. An implantable monitoring systemaccording to claim 11, wherein the heparin is both covalently andionically bound to the exterior surface of the outer membrane.
 13. Animplantable monitoring system comprising:at least one sensor assembly;an outer membrane surrounding the sensor assembly, the outer membranehaving a break therein over at least a portion of the sensor assemblywherein the break forms a window extending completely through the outermembrane; a window cover located within the window; wherein the windowcover comprises 2-hydroxyethyl methacrylate (HEMA); and methacrylic acid(MA); and a coating on the exterior surface of at least one of the outermembrane and window cover, which coating comprises polyethylene glycoland heparin.
 14. An implantable monitoring system according to claim 13,further comprising an enzyme solution between the sensor assembly andwindow cover.
 15. An implantable monitoring system according to claim14, wherein the enzyme solution comprises glucose oxidase.
 16. Animplantable monitoring system comprising:at least one sensor assembly;an outer membrane surrounding the sensor assembly, the outer membranehaving at least one break therein over a selected portion of the sensorassembly; wherein the break forms a window through the outer membrane;and wherein the outer membrane is permeable to a first selectedsubstance but is not substantially permeable to a second selectedsubstance; a window cover comprising a material permeable to both thefirst selected substance and the second selected substance; wherein thewindow cover material is located over only a portion of the sensorassembly; and wherein the surrounded sensor assembly a capable of beingimplanted in a living body.
 17. The system of claim 16, wherein thewindow cover material is located substantially only over the sensorassembly h the region of the break sensor assembly and the window cover.18. The system of claim 17, further comprising an enzyme positionedbetween the.
 19. The system of claim 18, wherein the system is used tomonitor glucose, the enzyme comprises glucose oxidase; the firstsubstance is oxygen, and the second substance is glucose.
 20. Animplantable monitoring system comprising:at least one sensor assembly;an outer membrane surrounding the sensor assembly; and a coating thatresists blood coagulation located on an exterior surface of the outermembrane; wherein the coating comprises a substance that is, in part,covalently bound to the outer membrane and, in part, ionically bound tothe outer membrane; and wherein the surrounded sensor assembly iscapable of being implanted in a living body.
 21. The system of claim 20,wherein the substance is heparin.
 22. The system of claim 20, whereinthe outer membrane has a break over a selected portion of the sensorassembly;wherein the break forms at least one window through the outermembrane; wherein the outer membrane is permeable to a first selectedsubstance and is not substantially permeable to a second selectedsubstance; and wherein the system additionally comprises: a window coverat least partially filling the window; wherein the window cover ispermeable to both the first substance and second substance.
 23. Thesystem of claim 22, further comprising an enzyme positioned between thesensor assembly and the window cover.
 24. The system or claim 23,wherein the system is used to monitor glucose, the enzyme comprisesglucose oxidase, wherein the first substance is oxygen, and wherein thesecond substance is glucose.
 25. The system of claim 21, wherein thecoating over the outer membrane additionally comprises polyethyleneglycol.
 26. An implantable monitoring system for sensing glucosecomprising:at least one sensor assembly; an outer membrane surroundingthe sensor assembly, the outer membrane having at least one breaklocated over a selected portion of the sensor assembly; wherein thebreak extends completely through the outer membrane and forms a windowthrough the outer membrane, and wherein the outer membrane is permeableto a first selected substance but is not substantially permeable toglucose; and a window cover at least partially filling the window,wherein the window cover is permeable to both the first substance and toglucose; and wherein the surrounded sensor assembly is capable of beingimplanted in a body of a patient.
 27. An implantable monitoring systemaccording to claim 26, further comprising an enzyme solution positionedbetween the sensor assembly and the window cover.
 28. An implantablemonitoring system according to claim 27, wherein the enzyme solutioncomprises glucose oxidase and the first substance is oxygen.
 29. Animplantable monitoring system according to claim 26, wherein the firstsubstance is oxygen.